Germline <em>BAP1</em> Inactivation Is Preferentially Associated with Metastatic Ocular Melanoma and Cutaneous-Ocular Melanoma Families

<div><h3>Background</h3><p><em>BAP1</em> has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional <em>BAP1</em> changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome.</p> <h3>Design</h3><p>To characterize <em>BAP1</em>'s contribution to melanoma risk, we sequenced <em>BAP1</em> in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds.</p> <h3>Results</h3><p>Germline <em>BAP1</em> mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the <em>BAP1</em> carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition.</p> <h3>Conclusion</h3><p>Germline <em>BAP1</em> mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of <u>c</u>utaneous/<u>o</u>cular <u>m</u>elanoma, atypical <u>m</u>elanocytic proliferations and <u>o</u>ther internal <u>n</u>eoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive <em>BAP1</em> inactivation.</p>